Abstract |
Multiple organ dysfunction (MOD) is the leading cause of mortality in septic patients with circulatory shock. Recent evidence suggests that the overproduction of the cytokine, tumor necrosis factor-alpha(TNF), and oxygen free radical molecules may mediate the progression of sepsis to MOD and death. In this study, we have examined the ability of MDL 101,002, a free radical scavenger, to reduce organ dysfunction and cytokine secretion induced by lipopolysaccharide (LPS) administration in rats. Treatment with MDL 101,002(10-60 ng/kg, i. p.) 30 min prior to an LPS challenge resulted in a dose-dependent reduction in several markers indicative of organ dysfunction and mortality. MDL 101,002 markedly decreased LPS-induced liver and kidney damage as indicated by serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) or urea and creatinine, respectively. MDL 101,002 also prevented LPS-induced pulmonary edema, but did not prevent leukopenia and only partially reduced thrombocytopenia. Associated with these improvements in organ dysfunction and survival was a modest decrease in LPS-stimulated interleukin-1 alpha (IL-1 alpha) and interleukin-1 beta (IL-1 beta) secretion and a marked ( > 90%) inhibition of TNF secretion by MDL 101,002. The data are consistent with a role for oxygen free radicals in the development of endotoxin-induced organ dysfunction and shock and suggest that free radical scavengers could reduce the mortality consequent to sepsis by decreasing organ dysfunction, at least in part, through a reduction in free radical stimulated cytokine secretion.
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Authors | T R Downs, R C Dage, J F French |
Journal | International journal of immunopharmacology
(Int J Immunopharmacol)
Vol. 17
Issue 7
Pg. 571-80
(Jul 1995)
ISSN: 0192-0561 [Print] England |
PMID | 8586485
(Publication Type: Journal Article)
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Chemical References |
- 3,4-dihydro-3,3-dimethylisoquinoline-N-oxide
- Antioxidants
- Cytokines
- Interleukin-1
- Interleukin-2
- Isoquinolines
- Lipopolysaccharides
- Nitrogen Oxides
- Tumor Necrosis Factor-alpha
- Aspartate Aminotransferases
- Alanine Transaminase
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Topics |
- Alanine Transaminase
(blood)
- Animals
- Antioxidants
(pharmacology)
- Aspartate Aminotransferases
(blood)
- Cell Survival
(drug effects)
- Cytokines
(biosynthesis)
- Escherichia coli
(metabolism)
- Interleukin-1
(biosynthesis)
- Interleukin-2
(biosynthesis)
- Isoquinolines
(pharmacology)
- Lipopolysaccharides
(antagonists & inhibitors, toxicity)
- Male
- Nitrogen Oxides
(pharmacology)
- Pulmonary Edema
(chemically induced, metabolism)
- Rats
- Rats, Sprague-Dawley
- Tumor Necrosis Factor-alpha
(biosynthesis)
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